title: HtrA1 sensitizes ovarian cancer cells to cisplatin-induced cytotoxicity by targeting XIAP for degradation.
abstract: HtrA1, a member of serine protease family, has been previously found to be involved in resistance to chemotherapy in ovarian cancer although the underlying mechanism is not clear. Using mixture-based oriented peptide library approach, previously we identified X-linked inhibitor of apoptosis protein (XIAP), a member of the inhibitor of apoptosis proteins family, as a potential substrate of HtrA1. The aim of our work is to investigate the link between HtrA1 and XIAP proteins and their relationships with chemoresistance in ovarian cancer. Our results showed that recombinant XIAP was degraded by purified wild-type HtrA1 but not mutant HtrA1 in vitro. Consistent with the in vitro data, coimmunoprecipitation assays showed that HtrA1 and XIAP formed a protein complex in vivo. Ectopic expression of HtrA1 led to decreased level of XIAP in OV167 and OV202 ovarian cancer cells, while knockdown of HtrA1 resulted in increased level of XIAP in SKOV3 ovarian cancer cells. Furthermore, overexpression of HtrA1 in OV202 cells promoted cell sensitivity to cisplatin-induced apoptosis that could be reversed by increased expression of XIAP. The cleavage of XIAP induced by HtrA1 was enhanced by cisplatin treatment. Taken together, our experiments have identified XIAP as a novel substrate of HtrA1 and the degradation of XIAP by HtrA1 contributes to cell response to chemotherapy, suggesting that restoring the expression of HtrA1 may be a promising treatment strategy for ovarian cancer.
authors.affiliation: Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: He
authors.forename: Ashwani
authors.initials: A
authors.lastname: Khurana
authors.forename: Jacie L
authors.initials: JL
authors.lastname: Maguire
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D002945:Cisplatin